WO2020128073A1 - Selenoprotein p in heart failure - Google Patents
Selenoprotein p in heart failure Download PDFInfo
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- WO2020128073A1 WO2020128073A1 PCT/EP2019/086844 EP2019086844W WO2020128073A1 WO 2020128073 A1 WO2020128073 A1 WO 2020128073A1 EP 2019086844 W EP2019086844 W EP 2019086844W WO 2020128073 A1 WO2020128073 A1 WO 2020128073A1
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- risk
- heart failure
- hospitalisation
- assessing
- mortality
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
- G01N2800/325—Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/50—Determining the risk of developing a disease
Definitions
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk of getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, in particular cardiovascular mortality, and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure, comprising a) determining the level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject, b) correlating the determined level and/or the amount of Selenoprotein P and/or fragments thereof in a subject having heart failure with (i) the risk for getting a cardiovascular event and/or (ii) with the risk of worsening heart failure condition and/or (iii) with the risk for mortality, in particular cardiovascular mortality, and/or
- Subject matter of the present invention includes stratification of patients and treatment methods for patients having heart failure at high risk (i) for getting a cardiovascular event and/or (ii) of worsening heart failure condition and/or (iii) for mortality, in particular cardiovascular mortality and/or (iv) ofhospitalisation or re-hospitalisation due to heart failure.
- Seppl Seppl
- SeP SeP
- SELF SePP
- SePP Selenoprotein P
- Gx glutathione peroxidases
- Heart failure was associated with lower selenium level (Kosar, Sahin et al. 2006) and serum selenium was reduced in African-American patients with congestive heart failure (Arroyo, Laguardia et al. 2006).
- Ghaemian et al. showed that serum selenium levels in congestive heart failure patients were similar to those of controls and the selenium levels did not correlate with the degree of left ventricular dysfunction (Ghaemian, Salehifar et al. 2012).
- selenium supplementation in general population and high cardiovascular disease risk population did not change all-cause mortality, cardiovascular disease mortality or cardiovascular events (Rees, Hartley et al. 2013).
- Selenium supplementation studies (Xia, Hill et al. 2005, Burk, Norsworthy et al. 2006, Meplan, Crosley et al. 2007) indicate that Selenoprotein P plasma level is the best easily accessible marker of human selenium nutritional status. A highly significant correlation was found between serum selenium and Selenoprotein-P levels (Andoh, Hirashima et al. 2005). However, once the nutritional requirement is met, Selenoprotein P level concentration does not reflect additional increases in selenium intake.
- Selenoprotein P is a secreted glycoprotein that contains most of the selenium in plasma (Read, Bellew et al. 1990, Hill, Xia et al. 1996). With respect to its selenium content, Selenoprotein P can be divided into two domains. The N-terminal domain, approximately two-thirds of the amino acid sequence, contains 1 selenocysteine (U) in a U-x-x-C redox motif. The shorter C-terminal domain contains multiple selenocysteines, e.g. nine in rats, mice, and humans.
- Selenoprotein P is present in plasma but so are shortened forms that have reduced selenium content.
- Selenoprotein P purified from rat plasma is present as four isoforms.
- shorter isoforms are present that terminate at the second, third, and seventh selenocysteine positions. These isoforms contain one, two, and six selenocysteine residues, respectively (Himeno, Chittum et al. 1996, Ma, Hill et al. 2002).
- human Selenoprotein P is a protein containing 381 amino acid residues (SEQ ID NO. 1) of which ten are predicted to be selenocysteine residues at positions 59, 300, 318, 330, 345, 352, 367, 369, 376 and 378. Its secreted form (after cleavage of the signal sequence) consists of 362 amino acid residues (SEQ ID NO. 2) and may contain post-translational modifications, which can include phosphorylation and multiple sites of glycosylation. Moreover, several fragments including fragments containing the N- or C-terminal part of Selenoprotein P have been identified (Hirashima, Naruse et al. 2003, Ballihaut, Kilpatrick et al. 2012).
- the liver produces most of the Selenoprotein P in plasma, where its turnover is rapid.
- Selenoprotein P is also expressed in other tissues and is presumably secreted by them (Hill, Lloyd et al. 1993, Yang, Hill et al. 2000). The liver acquires selenium from several sources and apportions it between selenoprotein synthesis and excretion from the organism.
- liver synthesizes its intrinsic selenoproteins as well as the secreted selenium molecules Selenoprotein P and excretory metabolites.
- Whole-body selenium thus, appears to be regulated in the liver by the distribution of metabolically available selenium between the pathways of selenoprotein synthesis and selenium excretory metabolite synthesis.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, in particular cardiovascular mortality, and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure, comprising a) determining the level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject and b) correlating the determined level and or the amount of Selenoprotein P and/or fragments thereof in a sample of a subject having heart failure with (i) the risk for getting a cardiovascular event and/or (ii) with the risk of worsening heart failure condition and/or (iii) with the risk for mortality (preferably the risk of mortality within one year), in particular cardiovascular mortality, in a subject having heart failure and or (iv) with the risk of hospitalisation or re-hospitalisation (preferably within 30 days) due to heart failure
- the risk in a subject having heart failure for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, in particular cardiovascular mortality, and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure is enhanced respectively if the level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject is decreased. In a particular embodiment said before mentioned risks are enhanced if the level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject is below a respective threshold.
- Risk for mortality may mean risk for cardiovascular mortality.
- Cardiovascular mortality means cardiovascular death related to stroke, myocardial infarction, or acute heart failure.
- said cardiovascular event may be selected from the group comprising acute decompensated heart failure, atherosclerosis, hypertension, cardiomyopathy and myocardial infarction and said cardiovascular mortality is selected from cardiovascular death related to myocardial infarction, or acute heart failure.
- said patient has a chronic heart failure, and that cardiovascular event is an acute decompensated heart failure.
- said cardiovascular event may be selected from the group comprising acute decompensated heart failure, atherosclerosis, hypertension, cardiomyopathy and myocardial infarction, but said cardiovascular event is not stroke and said cardiovascular mortality is selected from cardiovascular death related to myocardial infarction, or acute heart failure, but said cardiovascular mortality is not related to stroke.
- said cardiovascular event is an acute cardiovascular event selected from the group comprising myocardial infarction, acute decompensated heart failure, stroke, coronary re- vascularization and cardiovascular death related to myocardial infarction, stroke or acute heart failure.
- said cardiovascular event is an acute cardiovascular event selected from the group comprising myocardial infarction, acute decompensated heart failure, coronary re- vascularization and cardiovascular death related to myocardial infarction, or acute heart failure.
- said cardiovascular event is an acute cardiovascular event selected from the group comprising myocardial infarction, acute heart failure, coronary re-vascularization, but not stroke, and cardiovascular death related to myocardial infarction, or acute heart failure, but not related to stroke.
- Risk for getting a cardiovascular event and/or cardiovascular mortality means the risk of getting an event due to cardiovascular reasons or the risk of dying because of cardiovascular reasons within a certain period of time.
- said period of time is within 10 years, or within 8 years, or within 5 years or within 2.5 years, or within 1 year, or within 6 months, or within 3 months, or within 30 days, or within 28 days.
- Risk of a cardiovascular event or cardiovascular mortality means the risk of getting an event due to cardiovascular reasons or the risk of dying because of cardiovascular reasons within a certain period of time, but wherein the cardiovascular event or cardiovascular mortality is not stroke or related to stroke.
- said period of time is within 10 years, or within 8 years, or within 5 years or within 2.5 years, or within 1 year, or within 6 months, or within 3 months, or within 30 days, or within 28 days.
- Risk of a cardiovascular event or cardiovascular mortality means the risk of getting an event due to cardiovascular reasons or the risk of dying because of cardiovascular reasons within a certain period of time, but wherein the cardiovascular event or cardiovascular mortality is not stroke or related to stroke.
- said period of time is within 10 years, or within 8 years, or within 5 years or within 2.5 years, or within 1 year, or within 6 months, or within 3 months, or within 30 days, or within 28 days. It has been shown that the detection of Selenoprotein P can be used to assess the risk in a healthy subject for getting a first cardiovascular event or assessing the risk for cardiovascular mortality (PCT/EP2018/079030; Schomburg et al. 2018. JAMA Cardiology, submitted) by using a certain threshold (e.g. the median).
- the frequency distribution of Selenoprotein P in a healthy population ranges from 0.4 to 20.0 mg/L with a median concentration of 5.5 mg/L (Fig. 5A).
- Threshold ranges of Selenoprotein P to assess the risk of healthy subjects for getting a first cardiovascular event or cardiovascular mortality are between 4.0 and 5.5 mg/L.
- the Selenoprotein P concentration of the heart failure population is a much lower concentration ranging between 0.8 and 6.9 mg/L and a median of 3.0 mg/L, where the majority of values are well below a threshold for healthy subjects (e.g. 97.3% of heart failure patients are below 5.5 mg/L and 79.7% of heart failure patients are below 4.0 mg/L) (Fig. 5B).
- Heart failure patients have Selenoprotein P concentrations that are compareable to healthy patients having a risk of getting a cardiovascular event, as those patients have already suffered a cardiovascular event (namely heart failure).
- the low Selenoprotein P concentrations in heart failure patients can further be divided into subgroups, whereas Selenoprotein P concentrations at the lower end of the distribution in heart failure patients have a higher risk of e.g. worsening heart failure or rehospitalization due to heart failure or mortality according to the present invention.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality, in particular cardiovascular mortality, and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure, comprising a) determining the level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject and b) comparing the determined level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject to a reference level of Selenoprotein P and/ or fragments thereof of a reference level.
- reference level is well known in the art. Preferred reference levels can be determined by the skilled person without further ado.
- the term “reference level” herein refers to a predetermined value for the respective biomarker.
- level encompasses the absolute amount, the relative amount or concentration as well as any value or parameter which correlates thereto or can be derived therefrom.
- the reference level is a level which allows for allocating the subject into a group of subjects who are at risk of e.g. getting a cardiovascular event, or into a group of subjects who are not at risk of e.g. getting a cardiovascular event.
- the reference level shall allow for differentiating between a subject who is at risk or who is not at risk of e.g. getting a cardiovascular event.
- the reference level is predetermined and set to meet routine requirements in terms of e.g. specificity and/or sensitivity. These requirements can vary, e.g. from regulatory body to regulatory body. It may for example be that assay sensitivity or specificity, respectively, has to be set to certain limits, e.g. 80%, 90%, 95% or 98%, respectively. These requirements may also be defined in terms of positive or negative predictive values. Nonetheless, based on the teaching given in the present invention it will always be possible for a skilled artisan to arrive at the reference level meeting those requirements.
- the reference level is determined in a reference sample or samples from a patient (or group of patients) who are at risk. In another embodiment, the reference level is determined in a reference sample or samples from a patient (or group of patients) who are not at risk of e.g. getting a cardiovascular event.
- the reference level in one embodiment has been predetermined in reference samples from the disease entity to which the patient belongs. In certain embodiments the reference level can e.g. be set to any percentage between 25% and 75% of the overall distribution of the values in a disease entity investigated. In other embodiments the reference level can e.g. be set to the median, tertiles or quartiles as determined from the overall distribution of the values in reference samples from a disease entity investigated.
- the reference level is set to the median value as determined from the overall distribution of the values in a disease entity investigated.
- the reference level may vary depending on various physiological parameters such as age, gender or subpopulation, as well as on the means used for the determination of Selenoprotein P or fragments thereof referred to herein.
- a reference level may be determined by measuring Selenoprotein P or fragments thereof in a reference population.
- a reference population may be a healthy population, e.g. with no signs and symptoms of heart failure.
- a reference population may be a population of subjects suffering from a disease or disorder, in particular heart failure patients.
- a reference population may consist of more than one reference subjects.
- An example of a healthy reference population with respective Selenoprotein P concentrations is given in Schomburg et al. (Schomburg et al. 2018. JAMA Cardiology, submitted).
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of re-hospitalisation due to heart failure as above outlined, wherein (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure is enhanced when the determined level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject is below a threshold.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality and/or (iv) the risk of hospitalisation or re hospitalisation due to heart failure is enhanced when said level and/or the amount of Selenoprotein P and/or fragments thereof in said sample is below a threshold, wherein said threshold is between 2.0 and 4.4 mg/L, preferably between 2.3 and 3.8 mg/L, more preferably between 2.6 and 3.4 mg/L, more preferably between 3.0 and 3.3 mg/L, most preferred said threshold is 3.3 mg/L.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of re-hospitalisation due to heart failure as above outlined, wherein (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality and/or (iv) the risk of re-hospitalisation due to heart failure is enhanced when said level and/or the amount of Selenoprotein P and/or fragments thereof in said sample is below a threshold, wherein said threshold has been determined by the calculation of receiver operating characteristic curves (ROC curves), plotting the true positive rate (sensitivity,’’disease” population e.g. subjects who did develop the condition) against the false positive rate (1 -specificity,’’normal” population e.g. subjects
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of re-hospitalisation due to heart failure as above outlined, wherein (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality and/or (iv) the risk of re-hospitalisation due to heart failure is enhanced when said level and/or the amount of Selenoprotein P and/or fragments thereof in said sample is below a threshold, wherein said threshold is below 4.4 mg/L, preferably below 3.8 mg/L even more preferably below 3.4 mg/L, most preferred equal to or below 3.3 mg/L.
- a threshold range is useful between 2.2 and 4.4 mg/L.
- These thresholds are related to the calibration method mentioned in the examples. All thresholds and values have to be seen in relation to the test and the calibration used according to the Examples. A person skilled in the art may know that the absolute value of a threshold might be influenced by the calibration used. This means that all values and thresholds given herein are to be understood in context of the calibration used. Threshold levels may be determined by measuring samples from subjects who did develop a certain condition (e.g. a cardiovascular event) and samples from subjects who did not develop the condition. One possibility to determine a threshold is the calculation of receiver operating characteristic curves (ROC curves), plotting the true positive rate (sensitivity,’’disease” population, e.g.
- ROC curves receiver operating characteristic curves
- a threshold is selected, above which (or below which, depending on how a marker changes with the“disease”) the test is considered to be abnormal and below which the test is considered to be normal.
- the area under the ROC curve (AUC) is a measure of the probability that the perceived measurement will allow correct identification of a condition.
- a threshold is selected to provide an AUC of greater than about 0.5, more preferably greater than about 0.7, still more preferably greater than about 0.8, even more preferably greater than about 0.85, and most preferably greater than about 0.9.
- the term“about” in this context refers to +1-5% of a given measurement.
- the horizontal axis of the ROC curve represents (1 -specificity), which increases with the rate of false positives.
- the vertical axis of the curve represents sensitivity, which increases with the rate of true positives. Thus, for a particular cut-off selected, the value of (1 -specificity) may be determined, and a corresponding sensitivity may be obtained.
- the AUC is a measure of the probability that the measured marker level will allow correct identification of a disease or condition. Thus, the AUC can be used to determine the effectiveness of the test.
- the odds ratio (OR) is a measure of effect size, describing the strength of association or non-independence between two binary data values (e.g. the ratio of the odds of an event occurring in test negative group to the odds of it occurring in the test positive group).
- Threshold levels can be obtained for instance from a Kaplan-Meier analysis, where the occurrence of a disease or the probability of a serious condition and/or death is correlated with the e.g. quartiles of the respective markers in the population. According to this analysis, subjects with marker levels above the 75th percentile have a significantly increased risk for getting the diseases according to the invention. This result is further supported by Cox regression analysis with adjustment for classical risk factors. The highest (or lowest quartile, depending on how a marker changes with the“disease”) versus all other subjects is highly significantly associated with increased risk for getting a disease or the probability of a serious condition and/or death according to the invention. Other preferred threshold values are for instance the 10th, 5th or 1st percentile of a reference population.
- the subject is male.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hostoryi sation due to heart failure as above outlined, wherein said cardiovascular event is selected from a group comprising myocardial infarction, stroke, coronary re-vascularization and said mortality is cardiovascular mortality.
- Subject matter of the present invention is a method for assessing a risk in a patient having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said cardiovascular mortality is selected from cardiovascular death related to myocardial infarction, stroke or acute heart failure.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said level and/or amount of Selenoprotein P and/or fragments thereof has been determined by an immunoassay using at least one binder binding to SEQ ID No. 2.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said at least one binder is an antibody or a fragment thereof.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said level and/or amount of Selenoprotein P and/or fragments thereof has been determined by mass spectroscopy.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hostoryi sation due to heart failure as above outlined, wherein said risk for getting a cardiovascular event including death is assessed for a period of time of up to one year.
- Subject matter of the present invention is a method for assessing a risk in a subject having heat failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said (ii) risk of worsening heart failure condition and/or (iii) the risk for mortality in said subject is assessed for a period of time of up to one year.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hostoryi sation due to heart failure as above outlined, wherein said risk of hospitalisation or re-hospitalisation due to heart failure is assessed for a period of 30 days.
- Subject matter of the present invention is a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein the sample is a bodily fluid.
- a bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva.
- the sample is a bodily fluid selected from the group comprising whole blood, plasma, and serum.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein the determined level and/or the amount of Selenoprotein P and/or fragments thereof is below a threshold and wherein said threshold is between 2.0 and 4.4 mg/L, preferably between 2.3 and 3.8 mg/L, more preferably between 2.6 and 3.4 mg/L, more preferably between 3.0 and 3.3 mg/L, most preferred 3.3 mg/L.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein the determined level and/or the amount of Selenoprotein P and/or fragments thereof is below a threshold and wherein said threshold is between 2.0 and 4.4 mg/L, preferably between 2.3 and 3.8 mg/L, more preferably between 2.6 and 3.4 mg/L, more preferably between 3.0 and 3.3 mg/L, most preferred 3.3 mg/L, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein selenium is administered to said subject in a pharmaceutically acceptable amount.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hostoryisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein selenium is administered to said subject in a pharmaceutically acceptable amount, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein selenium is administered to said subject in a pharmaceutically acceptable amount and wherein the determined level and/or the amount of Selenoprotein P and/or fragments thereof is below a threshold and wherein said threshold is between 2.0 and 4.4 mg/L, and wherein selenium is administered to said subject in a pharmaceutically acceptable amount to reduce said risks.
- Subject matter of the present invention is selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hostoryisation due to heart failure, wherein such an enhanced risk is determined according to a method according to the present invention as outlined herein, wherein selenium is administered to said subject in a pharmaceutically acceptable amount and wherein the determined level and/or the amount of Selenoprotein P and/or fragments thereof is below a threshold and wherein said threshold is between 2.0 and 4.4 mg/L, and wherein selenium is administered to said subject in a pharmaceutically acceptable amount to reduce said risks, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to the invention is performed at least two times.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to the invention is performed at least two times, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to the invention is performed as monitoring of said treatment.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to the invention is performed as monitoring of said treatment, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to the invention is performed and used for therapy-guidance.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to the invention is performed and used for therapy- guidance, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to any of the above embodiments is performed and used as companion diagnostics.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein a method for assessing said risk according to any of the above embodiments is performed and used as companion diagnostics, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein the selenium administered is selected from the group comprising selenite, selenate or selenomethionine (L-selenomethionine).
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein the selenium administered is selected from the group comprising selenite, selenate or selenomethionine (L- selenomethionine) , wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hostoryisation due to heart failure according to any of the above-outlined embodiments, wherein the selenium administered is selected from the group comprising selenite, selenate or selenomethionine (L-selenomethionine) in combination of anti-oxidant co-enzyme Q10 as an essential co-enzyme.
- the selenium administered is selected from the group comprising selenite, selenate or selenomethionine (L-selenomethionine) in combination of anti-oxidant co-enzyme Q10 as an essential co-enzyme.
- Subject matter of the present invention is a method of treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure according to any of the above-outlined embodiments, wherein the selenium administered is selected from the group comprising selenite, selenate or selenomethionine (L-selenomethionine) in combination of anti-oxidant co-enzyme Q10 as an essential co-enzyme, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- the above-mentioned methods for assessing said risks are used including threshold ranges as above mentioned.
- One threshold may be selenium levels equal or ⁇ 100 pg/L.
- subject refers to a living human or non-human organism.
- the subject is a human subject.
- the subject is suffering from heart failure.
- the term“decreased level” means a level below a certain threshold level.
- the term“increased level” means a level above a certain threshold level.
- determining the level of Selenoprotein P means that usually the immunoreactivity towards a region within the before mentioned molecules is determined. This means that it is not necessary that a certain fragment is measured selectively. It is understood that a binder which is used for the determination of the level of Selenoprotein P and/or fragments thereof binds to any fragment that comprises the region of binding of said binder. Said binder may be an antibody or antibody fragment or a non-IgG Scaffold.
- the level of Selenoprotein P is measured with an immunoassay and said binder is an antibody, or an antibody fragment binding to Selenoprotein P and/or fragments thereof.
- immunoassays are known and may be used for the assays and methods of the present invention, these include: radioimmunoassays ("RIA”), homogeneous enzyme- multiplied immunoassays (“EMIT”), enzyme linked immunoadsorbent assays (“ELISA”), apoenzyme reactivation immunoassay (“ARIS”), chemiluminescence- and fluorescence- immunoassays, Luminex-based bead arrays, protein microarray assays, and rapid test formats such as for instance immunochromatographic strip tests (“dipstick immunoassays”) and immuno-chromatography assays.
- RIA radioimmunoassays
- EMIT enzyme- multiplied immunoassays
- ELISA enzyme linked immunoadsorbent assays
- ARIS apoenzyme reactivation immunoassay
- chemiluminescence- and fluorescence- immunoassays chemiluminescence- and fluorescence- immunoassays
- such an assay is a sandwich immunoassay using any kind of detection technology including but not restricted to enzyme label, chemiluminescence label, electrochemiluminescence label, preferably a fully automated assay.
- such an assay is an enzyme labeled sandwich assay. Examples of automated or fully automated assay comprise assays that may be used for one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Centauer®, Brahms Kryptor®, Biomerieux Vidas®, Alere Triage®.
- it may be a so-called POC-test (point-of-care) that is a test technology which allows performing the test within less than one hour near the patient without the requirement of a fully automated assay system.
- POC-test point-of-care
- One example for this technology is the immunochromatographic test technology.
- At least one of said two binders is labeled in order to be detected.
- said label is selected from the group comprising chemiluminescent label, enzyme label, fluorescence label, radioiodine label.
- the assays can be homogenous or heterogeneous assays, competitive and non-competitive assays.
- the assay is in the form of a sandwich assay, which is a noncompetitive immunoassay, wherein the molecule to be detected and/or quantified is bound to a first antibody and to a second antibody.
- the first antibody may be bound to a solid phase, e.g. a bead, a surface of a well or other container, a chip or a strip, and the second antibody is an antibody which is labeled, e.g.
- the assay comprises two capture molecules, preferably antibodies which are both present as dispersions in a liquid reaction mixture, wherein a first labelling component is attached to the first capture molecule, wherein said first labelling component is part of a labelling system based on fluorescence- or chemiluminescence-quenching or amplification, and a second labelling component of said marking system is attached to the second capture molecule, so that upon binding of both capture molecules to the analyte a measurable signal is generated that allows for the detection of the formed sandwich complexes in the solution comprising the sample.
- said labeling system comprises rare earth cryptates or rare earth chelates in combination with fluorescence dye or chemiluminescence dye, in particular a dye of the cyanine type.
- fluorescence based assays comprise the use of dyes, which may for instance be selected from the group comprising FAM (5-or 6-carboxyfluorescein), VIC, NED, Fluorescein, Fluoresceinisothiocyanate (FITC), IRD- 700/800, Cyanine dyes, such as CY3, CY5, CY3.5, CY5.5, Cy7, Xanthen, 6-Carboxy- 2’, 4’, 7’ ,4, 7 -hexachlorofluorescein (HEX), TET, 6-Carb oxy-4’ , 5’ -dichloro-2’ ,
- chemiluminescence based assays comprise the use of dyes, based on the physical principles described for chemiluminescent materials in (Kirk- Othmer, Encvclovedia of chemical technology, 4th ed combat executive editor, J I Kroschwitz; editor, M Howe-Grant, John Wiley & Sons, 1993, vol.15, v. 518-562, incorporated herein by reference, including citations on vases 551-562).
- Chemiluminescent label may be acridinium ester label, steroid labels involving isoluminol labels and the like.
- Preferred chemiluminescent dyes are acridiniumesters.
- Enzyme labels may be lactate dehydrogenase (LDH), creatine kinase (CPK), alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), acid phosphatase, glucose-6-phosphate dehydrogenase and so on.
- LDH lactate dehydrogenase
- CPK creatine kinase
- AST aspartate aminotransferase
- ALT alanine aminotransferase
- acid phosphatase glucose-6-phosphate dehydrogenase and so on.
- the assay sensitivity of said assay is ⁇ 0.100 mg/L, preferably ⁇ 0.05 mg/L and more preferably ⁇ 0.01 mg/L.
- the diagnostic binder to Selenoprotein P and/or fragments thereof is selected from the group consisting of antibodies e.g. IgG, a typical full-length immunoglobulin, or antibody fragments containing at least the F -variable domain of heavy and/or light chain as e.g.
- fragment antigen binding including but not limited to Fab-fragments including Fab minibodies, single chain Fab antibody, monovalent Fab antibody with epitope tags, e.g. Fab-V5Sx2; bivalent Fab (mini-antibody) dimerized with the C3 ⁇ 4 domain; bivalent Fab or multivalent Fab, e.g. formed via multimerization with the aid of a heterologous domain, e.g. via dimerization of dHLX domains, e.g.
- Fab-dHLX-FSx2 F (ab‘ )2-fragments, scFv-fragments, multimerized multivalent or/and multispecific scFv-fragments, bivalent and/or bispecific diabodies, BITE® (bispecific T-cell engager), trifunctional antibodies, polyvalent antibodies, e.g. from a different class than G; single-domain antibodies, e.g. nanobodies derived from camelid or fish immunoglobulines.
- the level of Selenoprotein P and/or fragments thereof are measured with an assay using binders selected from the group comprising an antibody, an antibody fragment, aptamers, non-Ig scaffolds as described in greater detail below binding to Selenoprotein P and/or fragments thereof.
- an“assay” or“diagnostic assay” can be of any type applied in the field of diagnostics. Such an assay may be based on the binding of an analyte to be detected to one or more capture probes with a certain affinity. Concerning the interaction between capture molecules and target molecules or molecules of interest, the affinity constant is greater than 10 7 M 1 , preferred 10 8 M 1 , more preferred greater than 10 9 M 1 , most preferred greater than 10 10 M 1 . Binding affinity may be determined using the Biacore method, offered as service analysis e.g. at Biaffin, Kassel, Germany (http://www.biaffin.com/de/ ' ).
- binding molecules are molecules which may be used to bind target molecules or molecules of interest, i.e. analytes (i.e. in the context of the present invention Selenoprotein P and fragments thereof), from a sample. Binder molecules must thus be shaped adequately, both spatially and in terms of surface features, such as surface charge, hydrophobicity, hydrophilicity, presence or absence of lewis donors and/or acceptors, to specifically bind the target molecules or molecules of interest.
- binder molecules may for instance be selected from the group comprising a nucleic acid molecule, a carbohydrate molecule, a PNA molecule, a protein, an antibody, a peptide or a glycoprotein.
- the binder molecules are antibodies, including fragments thereof with sufficient affinity to a target or molecule of interest, and including recombinant antibodies or recombinant antibody fragments, as well as chemically and/or biochemically modified derivatives of said antibodies or fragments derived from the variant chain with a length of at least 12 amino acids thereof.
- Non-Ig scaffolds may be protein scaffolds and may be used as antibody mimics as they are capable to bind to ligands or antigenes.
- Non-Ig scaffolds may be selected from the group comprising tetranectin-based non-Ig scaffolds ( e.g . described in US 2010/0028995 ), fibronectin scaffolds (e.g. described in EP 1266 025: lipocalin-based scaffolds (e.g.
- ubiquitin scaffolds e.g. described in WO 2011/154420: ubiquitin scaffolds (e.g. described in WO 2011/073214). transferring scaffolds (e.g. described in US 2004/0023334 ), protein A scaffolds (e.g. described in EP 2231860), ankyrin repeat based scaffolds (e.g. described in WO 2010/060748). microproteins preferably microproteins forming a cystine knot) scaffolds (e.g. described in EP 2314308). Fyn S3 ⁇ 4 domain based scaffolds (e.g. described in WO 2011/023685) EGFR-A-domain based scaffolds (e.g. described in WO 2005/040229) and Kunitz domain based scaffolds (e.g. described in EP 1941867).
- transferring scaffolds e.g. described in US 2004/0023334
- protein A scaffolds e.g. described in EP 2231860
- ankyrin repeat based scaffolds e.g.
- At least one of said two binders is bound to a solid phase as magnetic particles, and polystyrene surfaces.
- the level of any of the above analytes may be determined by other analytical methods e.g. mass spectroscopy.
- At least one further biomarker is determined in the bodily fluid of a subject having heart failure and correlated with said (i) risk for getting a cardiovascular event and/or (ii) said risk of worsening heart failure condition and/or (iii) said risk for mortality and/or (iv) said risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said additional biomarker is selected from the group comprising: pro-Neurotensin 1-117 (PNT 1-117), C -reactive protein (CRP), pro-brain natriuretic peptide 1-108 (proBNP 1-108, NT-proBNP), proBNP, BNP, pro -atrial natriuretic peptide 1-98 (proANP-N-terminal fragment), pro-ANP and fragments thereof of at least five amino acids in length (e.g.
- MR-proANP adrenomedullin, pro-adrenomedullin (pro ADM) and fragments thereof of at least five amino acids in length
- MR-proADM adrenomedullin, pro-adrenomedullin
- fragments thereof of at least five amino acids in length e.g. MR-proADM
- ST-2 GDF15, Galectin-3, copeptin
- hGH human growth hormone
- fasting blood or plasma glucose triglycerides
- HDL cholesterol or subtractions thereof LDL cholesterol or subfractions thereof
- insulin cystatin C, selen, alanine-aminotranferase (ALT), aspartate- amino transferase (AST), bilirubin, alkaline phosphatase (ALP).
- ALT alanine-aminotranferase
- AST aspartate- amino transferase
- ALP alkaline phosphatase
- At least one further biomarker is determined in the bodily fluid of a subject having heart failure and correlated with said (i) risk for getting a cardiovascular event and/or (ii) said risk of worsening heart failure condition and/or (iii) said risk for mortality and/or (iv) said risk of hospitalisation or re-hospitalisation due to heart failure as above outlined, wherein said additional biomarker is selected from the group comprising: pro-Neurotensin 1-117 (PNT 1-117), C-reactive protein (CRP), pro-brain natriuretic peptide 1-108 (proBNP 1-108, NT-proBNP), proBNP, BNP, pro-atrial natriuretic peptide 1-98 (proANP-N-terminal fragment), pro-ANP and fragments thereof of at least five amino acids in length (e.g.
- MR-proANP adrenomedullin, pro-adrenomedullin (pro ADM) and fragments thereof of at least five amino acids in length
- MR-proADM adrenomedullin, pro-adrenomedullin
- fragments thereof of at least five amino acids in length e.g. MR-proADM
- ST-2 GDF15, Galectin-3, copeptin
- human growth hormone (hGH) human growth hormone
- hGH human growth hormone
- fasting blood or plasma glucose triglycerides
- HDL cholesterol or subfractions thereof LDL cholesterol or subfractions thereof
- insulin cystatin C, selen, alanine-aminotranferase (ALT), aspartate-amino transferase (AST), bilirubin, alkaline phosphatase (ALP), wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- ALT alanine-aminotranferase
- Subject matter of the present invention is also a method for determining in a subject having heart failure the risk as defined in any of the preceding paragraphs: (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality and/or (iv) the risk hospitalisation or of re-hospitalisation due to having heart failure, wherein said method is performed in order to stratify said subjects into risk groups as further defined below.
- Subject matter of the present invention is also a method for determining in a subject having heart failure the risk as defined in any of the preceding paragraphs: (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality and/or (iv) the risk hospitalisation or of re-hospitalisation due to having heart failure, wherein said method is performed in order to stratify said subjects into risk groups as further defined below, wherein the cardiovascular event is not stroke and wherein the cardiovascular mortality is not related to stroke.
- the methods are used in order to stratify the subjects into risk groups, e.g. those with a low risk, medium risk, or high.
- Low risk means that the value of Selenoprotein P and/or fragments thereof is substantially not decreased compared to a predetermined value in subjects who (i) did not get a cardiovascular event and/or (ii) did not get worsening heart failure condition and/or (iii) did not die within a certain period of time and/or (iv) did not get hospitalized or re-hospitalised due to heart failure.
- Fragments of Selenoprotein P may be selected from the group comprising SEQ ID No. 3 to 15.
- a preventive therapy or intervention is the supplementation with selenium.
- Selenium may be applied as selenite, selenate or selenomethionine (L-selenomethionine).
- the supplementation with selenium may be applied in combination with vitamins (e.g. vitamin E, vitamin C, vitamin A) and/or mineral nutrients (e.g. iodine, fluoride, zinc) and/or co -factors (e.g. coenzyme Q10).
- vitamins e.g. vitamin E, vitamin C, vitamin A
- mineral nutrients e.g. iodine, fluoride, zinc
- co -factors e.g. coenzyme Q10
- Myocardial infarction commonly known as a heart attack, occurs when blood flow decreases or stops to a part of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort, which may travel into the shoulder, arm, back, neck, or jaw.
- Myocardial infarction can be divided into ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI).
- Heart failure is a cardiac condition that occurs, when a problem with the structure or function of the heart impairs its ability to supply sufficient blood flow to meet the body's needs. It can cause a large variety of symptoms, particularly shortness of breath at rest or during exercise, signs of fluid retention such as pulmonary congestion or ankle swelling and objective evidence of an abnormality of the structure or function of the heart at rest.
- Acute heart failure is defined as a rapid onset of signs and symptoms of heart failure resulting in the need for urgent therapy or hospitalisation.
- Acute heart failure can present as acute de novo heart failure (new onset of acute heart failure in a patient without previous cardiac dysfunction) or acute decompensation of chronic heart failure.
- Stroke is defined as an acute focal neurological deficit resulting from a cerebrovascular disease.
- the two main types of stroke are ischemic and hemorrhagic, accounting for approximately 85% and 15%, respectively.
- the herein disclosed methods for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, in particular cardiovascular mortality, and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure, are not those, wherein stroke is the cardiovascular event or wherein the cardiovascular mortality is related to stroke.
- Coronary re- vascularization includes percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).
- Percutaneous coronary intervention is a non-surgical procedure used to treat narrowing (stenosis) of the coronary arteries of the heart found in coronary artery disease. After accessing the blood stream through the femoral or radial artery, the procedure uses coronary catheterization to visualize the blood vessels on X-ray imaging. After this, an interventional cardiologist can perform a coronary angioplasty, using a balloon catheter in which a deflated balloon is advanced into the obstructed artery and inflated to relieve the narrowing; certain devices such as stents can be deployed to keep the blood vessel open. Various other procedures can also be performed.
- Coronary artery bypass surgery also known as CABG surgery, and colloquially heart bypass or bypass surgery, is a surgical procedure to restore normal blood flow to an obstructed coronary artery. This surgery is often indicated when coronary arteries have a 50% to 99% obstruction.
- Subject matter of the present invention is also the supplementation with selenium in subjects identified to be at high risk.
- Solid dosage formulations for selenium are, e.g. tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure, comprising a) determining the level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject, b) correlating the determined level and/or the amount of Selenoprotein P and/or fragments thereof in a subject having heart failure with (i) the risk for getting a cardiovascular event and/or (ii) with the risk of worsening heart failure condition and/or (iii) with the risk for mortality, and/or (iv) with the risk of hospitalisation or re-hospitalisation due to heart failure.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality, and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to item 1, wherein in a subject having heart failure (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure is enhanced, when the determined level and/or the amount of Selenoprotein P and/or fragments thereof in a sample of said subject is below a threshold.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality, and/or (iv) assessing the risk of hospitalisation or re-hospitalisation in due to heart failure according to item 1 or 2, wherein in a subject having heart failure (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, and/or (iv) the risk of hospitalisation or re-hospitalisation due to heart failure is enhanced when said and/or the amount of Selenoprotein P and/or fragments thereof in said sample is below a threshold, wherein said threshold is between 2.0 and 4.4 mg/L, preferably between 2.3 and 3.8 mg/L, more preferably between 2.6 and 3.4 mg/L, more preferably between 3.0 and 3.3 mg/L, most preferred said threshold is 3.3 mg/L.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality, and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-3, wherein in a subject having heart failure (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, and/or (iv) the risk of hospitalisation or re hospitalisation due to heart failure is enhanced when said level and/or the amount of Selenoprotein P and/or fragments thereof in said sample is below a threshold, wherein said threshold has been determined by the calculation of receiver operating characteristic curves (ROC curves), plotting the true positive rate (sensitivity,’’disease” population e.g.
- ROC curves receiver operating characteristic curves
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality, and/or (iv) assessing the risk of hospitalisation or re-hostoryisation due to heart failure according to any of items 1-4, wherein in a subject having heart failure (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality, and/or (iv) the risk of hospitalisation or rehospitalisation due to heart failure is enhanced when said level and/or the amount of Selenoprotein P and/or fragments thereof in said sample is below a threshold, wherein said threshold is the lower range of a heart failure population e.g
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and or (iii) assessing the risk for mortality, and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-5, wherein said cardiovascular event is selected from a group comprising myocardial infarction, stroke, coronary re-vascularization, and heart failure and said mortality is cardiovascular mortality.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-6, wherein said mortality is cardiovascular mortality related to myocardial infarction, stroke or acute heart failure.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-7, wherein said level and/or amount of Selenoprotein P and/or fragments thereof has been determined by an immunoassay using at least one binder binding to SEQ ID No. 2.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to item 8, wherein said at least one binder is an antibody or a fragment thereof.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-7, wherein said level and/or amount of Selenoprotein P and/or fragments thereof has been determined by mass spectroscopy.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-10, wherein said (i) risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) said risk for mortality is assessed for a period of time. 12.
- a method for assessing (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality in a subject having heart failure and/or (iv) assessing the risk of re-hospitalisation in a hospitalized subject having heart failure according to any of items 1-11, wherein said (i) risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) the risk for mortality in a subject having heart failure is assessed for a period of time of up to 1 year.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-12, wherein said risk of hospitalisation or re-hospitalisation due to heart failure is assessed for a period of up to 30 days.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-13, wherein the sample is a bodily fluid.
- a method for assessing a risk in a subject having heart failure that is (i) the risk for getting a cardiovascular event and/or (ii) the risk of worsening heart failure condition and/or (iii) assessing the risk for mortality and/or (iv) assessing the risk of hospitalisation or re-hospitalisation due to heart failure according to any of items 1-14, wherein the sample is a bodily fluid selected from the group comprising whole blood, plasma, and serum.
- Selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure.
- Selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of hospitalisation or re-hospitalisation due to heart failure as determined according to a method of any of items 1-15.
- Selenium for use in treatment of a subject having heart failure and having an enhanced risk for (i) getting a cardiovascular event and/or (ii) having an enhanced risk for worsening heart failure condition and/or (iii) having an enhanced risk for mortality and/or (iv) having an enhanced risk of re-hospitalisation due to heart failure as determined according to a method of any of items 1-15, wherein the determined level and/or the amount of Selenoprotein P and/or fragments thereof is below a threshold and wherein said threshold is between 2.0 and 4.4 mg/L.
- the cardiovascular event is not stroke, and/or the cardiovascular mortality is not related to stroke.
- Figure 1 Distribution of SePP (mg/L) within groups based on outcomes. A) no re-hospitalisation/ survivor; B) re-hospitalised/survivor; C) no re-hospitalisation/deceased and D) re-hospitalised and deceased
- Example 1 Assay description The Selenotest ELISA (Hvbsier et al 2017. Redox Biolosv 11: 403-414; Hyhsier et al. 2015. Perspectives in Science 3: 23-24), a chromogenic enzyme-linked immunosorbent assay, for the quantitative determination of human S elenoproteinselenoprotein P in serum samples was used.
- the Selenotest ELISA is a sandwich enzyme immunoassay in 96 well plate format and uses two different S elenoproteinselenoprotein P specific monoclonal antibodies for the antigen capture and detection steps.
- the Selenoprotein P levels of the calibrators and controls were determined by measurements against serial dilutions of NIST SRM 1 50 Standard Reference Material.
- Monoclonal antibodies were generated by immunization of mice with an emulsion of purified recombinant Selenoprotein P.
- the specific monoclonal Ab5 was immobilized as capture- Ab, and the specific mAb2, was used as detection- Ab.
- the lower limit of quantification was determined at a Selenoprotein P level concentration of 11.6 pg/L, and the upper limit of quantification at 538.4 pg/L, thereby defining the working range at Selenoprotein P levels concentrations between 11.6 and 538.4 pg/L.
- the intersection at 20% CV defines the limit of detection, and was reached at a Selenoprotein P level concentration of 6.7 pg/L i.e., around 500-fold below average serum Selenoprotein P levels concentrations of well-supplied subjects.
- the signals were linear on dilution within the working range of the assay, and Selenoprotein P was stable in serum for 24h at room temperature.
- the Swedish Heart and Brain Failure Investigation study (HARVEST-Malmo) is a prospective, on-going study undertaken in consecutive patients hospitalized for acute heart failure (either newly diagnosed or exacerbated chronic heart failure) in Malmo, Sweden.
- the only exclusion criterion was the inability to deliver consent.
- Baseline data including blood sample donations and clinical examination were collected between March 2014 and September 2018 in 324 subjects. Complete data was available in 295 patients.
- Selenoprotein P was measured upon admission, along with clinical examination.
- BMI body mass index
- Subjects' health status (symptoms, function, and quality of life) was evaluated using Kansas City Cardiomyopathy Questionnaire (KCCQ), a valid and reliable measure of health status in both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction (Joseph, Novak et al. 2013) an instrument that has been validated in Swedish (Patel, Ekman et al. 2008).
- KCCQ Kansas City Cardiomyopathy Questionnaire
- Prevalent diabetes was defined as prior physician diagnosis of type 1 or type 2 diabetes, or use of antidiabetic medication.
- Atrial fibrillation (AF) was defined as prior diagnosis of HF.
- Prior congestive heart failure was defined as prior hospitalisation for congestive heart failure, or a physician diagnosis of heart failure prior to inclusion in the study.
- N-terminal pro-brain natriuretic peptide was analysed at the Department of Clinical Chemistry, Skane University Hospital in Malmd, participating in a national standardisation and quality control system using a sandwich assay based on ElectroChemiLuminiscence Immunoassay (Cobas, Roche Diagnostic, Basel, Switzerland).
- ElectroChemiLuminiscence Immunoassay Cobas, Roche Diagnostic, Basel, Switzerland.
- As for analyses of Selenoprotein P fasting blood samples were collected at admission in 4.5 ml EDTA-tubes and centrifuged at 1950 g for 10 minutes. Plasma was then aliquoted in 200m1 fractions into bar coded tubes (REMP, Brooks, Life Sciences, USA) and stored at -80°C until analysis.
- Selenoprotein P was analysed with a validated ELISA immunoassay using monoclonal antibodies as described in Example 1.
- KCCQ was used to quantify physical limitations, symptoms, self-efficacy, social interference and quality of life.
- An overall summary score ⁇ 50 was considered as an indication of low health-related quality of life, whereas overall summary scores >50 are an indication of better health-related quality of life (Soto, Jones et al. 2004).
- Total one-year mortality was defined as all-cause mortality within one year from study inclusion, and obtained from Swedish total population register Statistics Sweden.
- Re-hospitalisation was defined as first of any unplanned readmissions for worsening heart failure within 30 days from study inclusion. A composite endpoint of death or re-hospitalisation, whichever came first, within 30 days from study inclusion was created.
- NT-proBNP was the only variable with skewed distributions and therefore log transformed prior to analysis.
- KCCQ systolic blood pressure
- Cox regression models were carried out crude, in Model 1 (age and sex adjusted) and further adjusted for relevant risk factors in Model 2 (BMI, SBP, smoking, prevalent AF, prevalent diabetes, prior HF and log-transformed NT-proBNP) for one-year mortality, 30-day re-hospitalisation and a composite endpoint consisting of death or re-ho sali sation, whichever came first, within 30 days from study inclusion. Survival plots were computed using unadjusted Kaplan-Meier models. Length of hospital stay was analysed using crude linear regression models, adjusted for age and sex ⁇ Model 1) and further adjusted according to Model 2. All analyses were performed using IBM SPSS statistics version 25 (SPSS, Chicago, IL), except Harrell’s C-statistics analyses that were performed using R 3.4.3.
- ROC Receiver operating curves
- Adding Selenoprotein P to the variables in Model 2 increases the C-index from 0.584 to 0.632 (p for added value 0.002).
- Bootstrap corrected C-index for Model 2 is 0.507 (as none of the variables contributes to prediction).
- Adding Selenoprotein P increases the boostrap corrected 25 C-index to 0.561 (still less than Selenoprotein P alone, due to the penalty of adding 9 variables that have no predictive power).
- Selenoprotein P has been suggested to act as a selenium transporter and to be essential in selenium metabolism and storage (Saito and Takahashi 2002, Labunskyy, Lee et al. 201 1). In humans, levels of Selenoprotein P correlate with serum selenium levels (Andoh, Hirashima et al. 2005), and are usable as an index of the selenium BO nutritional status (Burk and Hill 2009). Selenium is an essential trace element that is involved in the control of the cell reduction-oxidation status and the immune system (McKenzie, Rafferty et al. 1998, Arthur, McKenzie et al. 2003, Huang, Rose et al.
- BMI body mass index
- KCCQ Kansas City Cardiomyopathy Questionnaire
- NT -proBNP N -terminal prohormone of brain natriuretic peptide
- SBP systolic blood pressure
- AF atrial fibrillation
- CHF congestive heart failure
- SePP Selenoprotein P.
- NT-proBNP 1.46 (1.07-1.98) 0.017 0.92 (0.70-1.19) 0.516 0.96 (0.75-1.23) 0.743
- hazard ratios HR and 95% confidence intervals.
- BMI body mass index
- SBP systolic blood pressure
- AF atrial fibrillation
- CHF congestive heart failure
- S ePP S elenoprotein P.
- the composite endpoint is defined as death or re-hospitalisation within 30 days from study inclusion, whichever came first.
- Model 1 is adjusted for age and sex.
- Model 2 is adjusted for age, sex, body mass index, systolic blood pressure, log-transformed NT-proBNP, smoking, prevalent atrial fibrillation, prevalent diabetes and prior CHF.
- Ql quartile with lowest levels of Selenoprotein P;
- Q4 quartile with highest levels of Selenoprotein P.
- Model 1 is adjusted for age and sex.
- Model 2 is adjusted for age, sex, body mass index, systolic blood pressure, log-transformed NT-proBNP, smoking, prevalent atrial fibrillation, prevalent diabetes and prior CHF.
- Table 4 Receiver operating curve (ROC) characteristics of Selenoprotein P thresholds for one-year mortality with respective sensitivities and specificities
- MPP Malmo Preventive Project
- the frequency distribution of Selenoprotein P in this healthy population ranges from 0.4 to 20.0 mg/L with a median concentration of 5.5 mg/L (Fig. 5A). Threshold ranges of
- the Selenoprotein P to assess the risk of healthy subjects for getting a first cardiovascular event or cardiovascular mortality are between 4.0 and 5.5 mg/L.
- the Selenoprotein P concentration of the heart failure population is a much lower concentration ranging between 0.8 and 6.9 mg/L and a median of 3.0 mg/L, where the majority of values are well below a threshold for healthy subjects (e.g. 97.3% of heart failure patients are below 5.5 mg/L and 79.7% of heart failure patients are below 4.0 mg/L) (Fig. 5B).
- Heart failure patients have Selenoprotein P concentrations that are compareable to healthy patients having a risk of getting a cardiovascular event, as those patients have already suffered a cardiovascular event (namely heart failure).
- the low Selenoprotein P concentrations in heart failure patients can further be divided into subgroups, whereas Selenoprotein P concentrations at the lower end of the distribution in heart failure patients have a higher risk of e.g. worsening heart failure or rehospitalization due to heart failure or mortality according to the present invention (see Example 2).
- SEQ ID NO. 1 Selenoprotein P including signal sequence (amino acid 1 to 381) MWRSLGLALA LCLLPSGGTE SQDQSSLCKQ PPAWSIRDQD PMLNSNGSVT
- SEQ ID NO. 2 secreted Selenoprotein P (amino acid 20 to 381)
- KNQAKKUEUP SN SEQ ID NO. 3 Selenoprotein P (amino acid 20 to 346)
- SEQ ID NO. 6 Selenoprotein P (amino acid 20 to 300)
- SEQ ID NO. 7 Selenoprotein P (amino acid 20 to 301)
- SEQ ID NO. 8 Selenoprotein P (amino acid 20 to 302)
- SEQ ID NO. 9 Selenoprotein P (amino acid 20 to 303) ESQDQSSLCK QPPAWSIRDQ DPMLNSNGSV TVVALLQASU YLCILQASKL
- SEQ ID NO. 10 Selenoprotein P (amino acid 20 to 304)
- SEQ ID NO. 11 Selenoprotein P (amino acid 20 to 305)
- SEQ ID NO. 12 Selenoprotein P (amino acid 20 to 306)
- SEQ ID NO. 14 Selenoprotein P (amino acid 279 to 381) KRCINQLLCK LPTDSELAPR SUCCHCRHLI FEKTGSAITU QCKENLPSLC
- SEQ ID NO. 15 Selenoprotein P (amino acid 312 to 381) TGSAITUQCK ENLPSLCSUQ GLRAEENITE SCQURLPPAA UQISQQLIPT EASASURUKN QAKKUEUPSN LITERATURE
Abstract
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AU2019408553A AU2019408553A1 (en) | 2018-12-20 | 2019-12-20 | Selenoprotein P in heart failure |
US17/415,242 US20220043005A1 (en) | 2018-12-20 | 2019-12-20 | Selenoprotein p in heart failure |
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BR112021010069A BR112021010069A2 (en) | 2018-12-20 | 2019-12-20 | Selenoprotein p in heart failure |
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WO2023275099A1 (en) | 2021-06-29 | 2023-01-05 | Berysol Gmbh | Composite biomarker for the identification of selenium deficiency in a bodily fluid |
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